p-(n-lower alkyl-n-dilower alkyl aminoethyl) aminobenzaldehyde isonicotinoyl hydrazone



e 2,828,314 iatented Mar. 25, 1958 ETHYL) AMINOBENZALDEHYDE ISONICOTIN-ov-L; HYDRAZONE.

Harry Louis Yale and Jack Bernstein, New Brunswick,

N. 1., assignors to Olin Mathieson Chemical Qorporation, New York, N.Y., a corporation of Virginia No Drawing. Application March'S, 1952Serial No. 275,682

2 Claims. or. 260-295) This invention relates to antimycobacterial,especially antituberculous, agents and methods for their preparation. I

The development of agents for the treatment of tuberculosis has beenreceiving extensive consideration for some time. Thus far, the mostwidely used have been streptomycin and dihydrostreptomycin. However,their utility has been limited owing to their toxicity, and patientsmust be watched carefully,-especially where prolonged treament isrequired, or where there is an impairmentof .kidney function. Auditorydamage has also been found to result from their use. Furthermore, theysuffer from the disadvantage that for optimum results they must beadministered by intermittent intramuscular injection rather thanperorally.

It is the object of this invention to provide a class of relativelynon-toxic antimycobacterial, especially antituberculous, agents (andmethods of preparing them) which are highly efficacious whenadministered perorally. The agents of this invention, which may also beused in the treatment of leprosy, comprise the following compounds andformulations thereof: I a

wherein X is the. residue of a monocyclic heterocycliccarboxylic(especiallya. pyridine-carboxylic or furoic) acid stripped'of itscarboxyl, group, Y is phenylene or substituted phenylene, E and Z eachrepresent hydrogen or together represent an additional N-C bond, and

T is a member of the group consisting of amino, alkylamino,aminoalkylamino and acylamino groups.

The compounds of this invention are heterocyclic carboxylic acidhydrazones (especially isonicotinic acid hydrazones) ofaminobenzaldehydes, and the corresponding N-heterocyclic-acyl N'substituted hydrazines.

r '2 acetamidobenzaldehyde, propionamidobenzaldehyde,stearoylamidobenzaldehyde, o-hydroxy-p aminobenzaldehyde,o-methyl-p-aminobenzaldehyde and N-methyl-N-diallrylaminoethyl-p-aminobenzaldehyde.

Wide latitude is permissible with respect to reaction conditions. Thus,in preparing the hydrazones, the proportions of reactants used may bealtered as desired; and, although water is preferred as the reactionmedium, other solvents such as the lower alkanols, dioxane, theCellosolvesand dimethylformamide, may be used.

The N-heterocyclic-acyl N-substituted hydrazines may be obtained byreduction of the corresponding hydrazones, which reduction is preferablyeffected by treatment with hydrogen in the presence of a catalyst, suchas platinum dioxide and palladium on charcoal until the required amountof hydrogen has been absorbed. The reduction may also be efiected bytreatment with nascent hydrogen provided by sodium in liquid ammonia,sodium amalgam, zinc-copper couple, etc.; or electrolytic reduction maybe used. More complete hydrogenation would not only result in saturationof the C=N but could also transform the heterocyclic nucleus tohydrogenated forms thereof (e. g. pyridine to piperidine). 'As solventin the hydrog'enation one may use, inter alia, a lower alkanol (e. g.methanol, ethanol, and isopropanol), water, acetic acid, dioXane andcyclohexanol. I

In synthesis of the N-heterocyclic-acyl N-substituted hydrazines, onemay prepare and isolate the hydrazone and then hydrogenate to obtain thedesired hydrazine; or one may carry out the hydrazone formation andhydrogenation thereof in a single step, or in the same reaction medium.

Acid-addition salts may be formed of those compounds of this inventionwhich contain a basic nitrogen atom, using conventional; methods. Thus,salts with mineral acids may be formed in aqueous solution orunderanhydrous conditions, for example, by passing hydrogen chloride gasinto an ethereal solution of the free base. Clearly, other salts, suchas those of sulfuric acid,,phosphoric acid, p-aminosalicylic acid,p-toluenesulfonic acid, methionine, sulfamic acid, lactic caid, citricacid, gluconic acid, etc., may be prepared;

' The compounds may be used perorally. as chemother apeutic agents fortuberculosis, or may be employed as environmental antituberculousagents, especially in hospitals and dairies. Thus, for peroraladministration, the

Following, in outline form, is the process by which the compounds of theinvention may be obtained:

' XCON'HNI- ICH Y wherein X, Y and T have the same meaning ashereinbefore given.

The hydrazones of this invention may be prepared by reacting aheterocyclic carboxylic acid hydrazide with the appropriateaminobenzaldehyde. Thus, the hydrazide reactant may be the hydrazide ofany heterocyclic acid such as nicotinic, isonicotinic, picolinic,furoic, thiophenecarboxylic, pyrrolecarboxylic, nip ecotic,isonipecotic,and pyrrolidine-carboxylic; and the aminobenzaldehyde reactants includethe unsubstituted amino benzaldehyde as 'well as N-substituted(especially para-N-substituted) and/ or C-substituted derivativesthereof, such as methylaminobenzaldehyde, dimethylaminobenzaldehyde,diethylaminobenzaldehyde, acetamidobenzaldehyde, monochlorcompounds maybe embodied in various pharmaceutical formulations, which term, as usedherein, includes dosage unit formulations as well as subdivisibleformulations of the compound in a suitable vehicle or carrier (e. g.,elixirs, suspensions, distilled-water solutions, saline solutions, etc).Preferred arethe dosage-unit formulations, as capsules and tablets.These may be prepared in the conventional manner. Thus, capsules may bemade containing a mixture of the compound and starch (or other suitableexcipient) in appropriate proportion. Also, onepiece gelatin capsulesmay be prepared containing the desired dosage in sufiicient corn oil torender the compound capsulatable. Tablets may be prepared to containdesired quantities of the compound, using lactose and starch, forexample, as excipients, and may be scored to enable one to takefractional dosages.

Therapeutic dosages of the compounds of this invention are readilydeterminable, peroral administration of the isonicotinoylhydrazone ofp-aminobenzaldehyde in a dosage of the order of 250 mg./kg. day beingtherapeutically effective.

In sterile aqueous solutiom'or in physiological saline solution, thecompound may be used for intrathecal injection or instilled into empyemacavities, large lung cavities, or draining fistulae.

ethanol, and the diluted mixture is heated to cause solution, thentreated with decolorizing charcoal (Darco),

the manner in which the novel products may be prepared:

' EXAMPLE 1 p-Acetamidobenzaldehyde isonicotinoylhydrazone A warmsolution of 13.7 g. isonicotinic acid hydrazide in 50 ml. water is mixedwith a solution of 16.3 g. p-.

acetamidobenzaldehyde in 250 ml; water. A precipitate forms almostimmediately. The reaction mixture is cooled in an ice'bath for at least'minutes to complete pre cipitation. and the solid material (M. P.292-294 C.) is isolated by filtration. Recrystallization from a mixtureof '480 ml. dimethylformamide and 120 ml. water yields about g. purifiedhydrazone (M. P. 292-294 EXAMPLE 2 p-Acetamidobenzalde hydfuroylhydrazone To a solution of 23.2 g. Z-furoic acid hydrazide in 200ml. warm water is added a solution of 32.6 g. p-acetamidobenzaldehyde,in 250 ml. warm 50% aqueous ethanol. The resulting pale yellow solutionis warmed gently on a steam bath for about 5 minutes, causing formationof a heavy, pale yellow precipitate. The precipitate is separated fromthe-warm reaction mixture by filtration, then washed with about 200 ml.warm 25% aqueous ethanol to obtain the crude product. The crude productis recrystallized from glacial acetic acid (50 ml./g.), filtered, thenwashed successively with water, ethanol and ethyl ether to obtain thepurified hydrazone in about 75% yield.

EXAMPLE 3 p Diethylaminobenzaldehyde isonicotin-oylhydrazorze To asolution of 27.4 g. isonicotinic acid hydrazide in 400 ml. wateris addeda solution of 35.4 g. p-diethylaminobenzald'ehyde in 150 ml. ethanol.The oil, which immediately separatesfrom the reaction mixture, becomesgranular on cooling. The reaction mixture is diluted with 250 ml.ethanol and the diluted mixture is heated to. cause solution, thentreated with decolorizing charcoal (Darco), and 'filtered while hot. Thegranular precipitate which forms on cooling is separated by filtrationto obtain about 43 g. crude product (M. P. 152-155? C.).Recrystallization from a mixture of 450 mlQethanoland 300 ml wateryields thepurified hydrazone (M. P. 180- 181 ,c.

- EXAMPLE 4 p-Dimethyiqminobenzaldehyde isonicotinoylhydrazone To asolution of 27.4 g. isonicotinic acid hydrazide in 500 ml. water isadded a solution of 29.8 g. p-dimethylaminobenzaldehyde in 2 00 .ml.ethanol. The oil which separates from the reaction mixture crystallizesimmedi at'ely. The reaction mixture is diluted with 250 m1.

and filtered while hot. The crystalline precipitate, which forms oncooling, is separated by filtration to obtain the crude product (M. P.198200 C.). Recrystallization from 50% aqueous ethanol yields thepurified hydrazone (M. P. 200-201 C.).

EXAMPLE 5 p-(N-methyl-N diethylaminoethyl)-aminobenzaldehydeisonicotinoylhydrazpne To a solution 0112.9 g. isonicotinic acidhydrazide in 500 ml. water is added 22 g. p-(N-methyl-N-dimethyLaminoethyl)raminobenzaldehyde, causing an oilto separate. This reactionmixture is then diluted with 200 ml. ethanol'and the diluted mixture isheated to cause solution, then treated with decolorizing charcoal(Darco), andpfilteredwhile hot. The crystalline precipitate which formson cooling and standing, is separated by filtration to obtain the crudeproduct (M. P.79-8l- C.). Recrystallization from 350ml. of a mixture of4:3 water-ethanol yields the purified hydrazone (M. P. 80-81" C.).

V EXAMPLE 6 V N-is'oni cotinoyl-N-(p diethylaminobenzyl)hydrazine I Asolution of 20 g. p-diethylaminobenzaldehyde isonicotinoylhydra'zone('cf. Example 3) in 150 ml. .warm absolute ethanol is treated withhydrogenat 70? C. and a pressure corresponding 'to' 250 cm. mercury withshaking, in'the'presen'ce'of; 100 mgiplatinum'dioxide. In approximately"5' hours, 0.127 g. hydrogen is absorbed. The catalyst is then separatedfrom th'efwarm' solution by filtration, and the resulting. solution isconcentrated to dryness under reduced pressure. The residue iscrystallized by trituration with'about 100 ml. dry ethyl ether to yieldthe" 'N-isonicotinoyl-N- (p-diethylaminobenzyDhydrazine.

' This invention may be variously otherwise embodied within'the scope ofthe appended claims.

We claim: s 1. Compounds of the formula References Cited in the file ofthis patent I Adkins: Reactions of Hydrogen (U'f o f Wis.),' p. 87(1946).

Mey r: Monat h. 1912).

fiir Chemie, vol. 33, pp. 400402 'Adkins: Reactions of Hydrogen (U. ofWise.), pp.

1. COMPOUNDS OF THE FORMULA